CeSPIACE: New peptide drug blocks COVID-19 variants

In a major scientific breakthrough, researchers from the Institute of Science Tokyo have developed a promising new drug candidate, CeSPIACE, that could offer broad protection against SARS-CoV-2 variants, including the highly transmissible Omicron XBB.1.5. The peptide-based inhibitor, consisting of just 39 amino acids, targets a critical region of the virus’s spike protein that is less prone to mutation, making it effective against evolving strains.

The study, led by Professor Yoshinori Fujiyoshi and Project Assistant Professor Shun Nakamura, was conducted in collaboration with the Department of Microbiology and Infection Control at Osaka Medical and Pharmaceutical University. The findings were published in the Proceedings of the National Academy of Sciences, marking a significant step toward creating a universal antiviral for COVID-19.

Targeting the invariant core

SARS-CoV-2, the virus responsible for COVID-19, infects human cells by binding its spike protein to angiotensin-converting enzyme 2 (ACE2) receptors on the surface of cells. While existing treatments attempt to block this interaction, the virus’s rapid mutation rate often allows it to evade these therapies.

CeSPIACE, short for COVID-19 Eliminative Short Peptide Inhibiting ACE2 Binding, takes a different approach. It binds to the receptor-binding domain (RBD) of the spike protein – a structurally critical part of the virus that is less likely to mutate due to its essential role in viral function. This strategic targeting increases the drug’s resilience to new variants.

“All pathogen proteins, like the SARS-CoV-2 spike, have invariant structures critical for their functions, making them good targets for mutation-tolerant drugs, as seen in our peptide engineering,” said Fujiyoshi.

Using advanced imaging techniques, including cryo-electron microscopy and X-ray crystallography, the research team identified key stable regions of the RBD. They then engineered CeSPIACE to form a two-helix bundle that self-assembles into a four-helix structure, maximizing its ability to bind to the spike protein and block ACE2 interaction.

CeSPIACE binds to the invariant region of the RBD in the spike protein, which is less likely to mutate, making it effective against mutant strains.

Impressive performance in lab and animal tests

CeSPIACE has demonstrated remarkable potency against multiple SARS-CoV-2 variants, including the wild-type strain, Alpha, Delta, and Omicron BA.5. Laboratory tests showed that the peptide binds to the spike protein with picomolar (pM) affinity, ranging from 44 pM to 928 pM – a measure of extremely strong binding.

In live animal studies, Syrian hamsters treated with CeSPIACE via a three-day intranasal regimen showed a 1,000-fold reduction in viral load compared to untreated controls when exposed to the Delta variant. In human lung cell cultures, CeSPIACE effectively blocked viral entry into pre-treated cells and prevented reinfection of already infected cells.

The ability of CeSPIACE to neutralise a wide range of variants highlights its potential as both a preventative and a therapeutic treatment. Its relatively simple peptide structure also makes it easier and cheaper to produce than complex biological antibodies, which are costly and require sophisticated production facilities.

Potential for future pandemics

Peptide-based drugs like CeSPIACE are not only effective but also chemically stable, meaning they do not require cold storage – a major advantage for global distribution. This could allow for rapid and affordable mass production during future outbreaks.

“Unknown infectious diseases will continue to emerge,” said Fujiyoshi. “Our strategy of engineering mutation-tolerant inhibitors can be applied to developing therapeutics against other existing infections or future pandemics.”

This breakthrough could facilitate the development of similar treatments against other viruses such as influenza and HIV, potentially transforming the future of antiviral medicine.

The study was published in the Proceedings of the National Academy of Sciences.